Background HLA-C is an important ligand for killer immunoglobulin like receptors (KIR) that regulate natural killer (NK) cell function. Based on KIR specificity HLA-C molecules are allocated into two groups, HLA-C1 or HLA-C2; HLA-C2 is more inhibiting to NK cell function than HLA-C1. We studied the clinical importance of HLA-C genotypes on the long-term graft survival of 760 kidney transplants performed at our centre utilising a population based genetic study and cell culture model to define putative mechanisms. Methods and Findings Genotyping was performed using conventional DNA PCR techniques and correlations made to clinical outcomes. We found that transplant recipients with HLA-C2 had significantly better long-term graft survival than transplant recipients with HLA-C1 (66% versus 44% at 10 years, log-rank p = 0.002, HR = 1.51, 95%CI = 1.16–1.97). In in-vitro NK and dendritic cell (DC) co-culture model we made several key observations that correlated with the population based genetic study. We observed that donor derived NK cells, on activation with IL-15, promoted differential HLA-C genotype dependent DC maturation. In NK-DC co-culture, the possession of HLA-C2 by DC was associated with anti-inflammatory cytokine production (IL-1RA/IL-6), diminished DC maturation (CD86, HLA-DR), and absent CCR7 expression. Conversely, possession of HLA-C1 by DC was associated with pro-inflammatory cytokine synthesis (TNF-α, IL-12p40/p70), enhanced DC maturation and up-regulation of CCR7 expression. By immunohistochemistry the presence of donor NK cells was confirmed in pre-transplant kidneys. Conclusions We propose that after kidney transplantation IL-15 activated donor derived NK cells interact with recipient DC with less activation of indirect allo-reactivity in HLA-C2 positive recipients than HLA-C1 positive recipients; this has implications for long-term graft survival. Early events following kidney transplantation involving NK-DC interaction via KIR and HLA-C immune synapse may have a central role in long-term kidney transplant outcomes.
References
[1]
Sayegh MH, Carpenter CB (2004) Transplantation 50 Years Later – Progress, Challenges, and Promises. N Engl J Med 351: 2761–2766.
[2]
2004 Annual report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: transplant data 1994–2003. Rockville, Md.: Health Resources and Services Administration, Division of Transplantation, 2004.
[3]
Meier-Kriesche HU, Schold JD, Kaplan B (2004) Long-term renal allograft survival: have we made significant progress or is it time to rethink our analytic and therapeutic strategies? Am J Transplant 4(8): 1289–95.
[4]
Paul LC (1999) Chronic allograft nephropathy: an update. Kidney Int 56: 783–793.
[5]
Jevnikar AM, Mannon RB (2008) Late kidney allograft loss: what we know about it, and what we can do about it. Clin J Am Soc Nephrol Suppl 2: S56–67.
[6]
Terasaki PI, Cai J (2008) Human leukocyte antigen antibodies and chronic rejection: from association to causation. Transplantation 86(3): 377–83.
[7]
Bestard O, Nickel P, Cruzado JM, Schoenemann C, Boenisch O, et al. (2008) Circulating alloreactive T cells correlate with graft function in longstanding renal transplant recipients. J Am Soc Nephrol 19(7): 1419–29.
Lanier LL (1998) NK cell receptors. Annu Rev Immunol 16: 359–393.
[10]
Parham P (2005) MHC class I molecules and KIRs in human history, health and survival. Nat Rev Immunol 5: 201–214.
[11]
Carrington M, Wang S, Martin MP, Gao X, Schiffman M, et al. (2005) Hierarchy of resistance to cervical neoplasiamediated by combinations of killer immunoglobulin-like receptor and human leukocyte antigen loci. J Exp Med 201: 1069–1075.
[12]
Hiby SE, Walker JJ, O'Shaughnessy KM, Redman CW, Carrington M, et al. (2004) Combinations of maternal KIR and fetal HLA-C genes influence the risk of pre-eclampsia and reproductive success. J Exp Med 200(8): 957–65.
[13]
Ahlenstiel G, Martin MP, Gao X, Carrington M, Rehermann B, et al. (2008) Distinct KIR/HLA compound genotypes affect the kinetics of human antiviral natural killer cell responses. J Clin Invest 118(3): 1017–1026.
[14]
Khakoo SI, Thio CL, Martin MP, Brooks CR, Gao X, et al. (2004) HLA and NK Cell Inhibitory Receptor Genes in Resolving Hepatitis C Virus Infection. Science 305: 872–874.
[15]
Hanvesakul R, Spencer N, Cook M, Gunson B, Hathaway M, et al. (2008) Donor HLA-C genotype has a profound impact on the clinical outcome following liver transplantation. Am J Transplant 8(9): 1931–41.
[16]
Kunert K, Seiler M, Mashreghi MF, Klippert K, Sch？nemann C, et al. (2007) KIR/HLA ligand incompatibility in kidney transplantation. Transplantation 84(11): 1527–33.
[17]
Nowak I, Majorczyk E, Wisniewski A, Pawlik A, Magott-Procelewska M, et al. (2010) Does the KIR2DS5 gene protect from some human diseases? PLoS One 5(8): e12381.
[18]
Tran TH, Mytilineos J, Scherer S, Laux G, Middleton D, et al. (2005) Analysis of KIR ligand incompatibility in human renal transplantation. Transplantation 80(8): 1121–3.
[19]
Trinchieri G (1989) Biology of natural killer cells. Adv Immunol 47: 187–376.
[20]
Jacobs R, Hintzen G, Kemper A, Beul K, Kempf S, et al. (2001) CD56bright cells differ in their KIR repertoire and cytotoxic features from CD56dim NK cells. Eur J Immunol 31(10): 3121–7.
[21]
Piccioli D, Sbrana S, Melandri E, Valiante NM (2002) Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells. J Exp Med 195(3): 335–41.
[22]
Gerosa F, Baldani-Guerra B, Nisii C, Marchesini V, Carra G, et al. (2002) Reciprocal activating interaction between natural killer cells and dendritic cells. J Exp Med 195(3): 327–33.
[23]
Ferlazzo G, Tsang ML, Moretta L, Melioli G, Steinman RM, et al. (2002) Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells. J Exp Med 195(3): 343–51.
[24]
Lucas M, Schachterle W, Oberle K, Aichele P, Diefenbach A (2007) Dendritic cells prime natural killer cells by trans-presenting interleukin 15. Immunity 26(4): 503–17.
[25]
Semino C, Angelini G, Poggi A, Rubartelli A (2005) NK/iDC interaction results in IL-18 secretion by DCs at the synaptic cleft followed by NK cell activation and release of the DC maturation factor HMGB1. Blood 106: 609–616.
[26]
Vitale M, Della Chiesa M, Carlomagno S, Pende D, Aricò M, et al. (2005) NK-dependent DC maturation is mediated by TNFalpha and IFNgamma released upon engagement of the NKp30 triggering receptor. Blood 106(2): 566–71.
[27]
Brilot F, Strowig T, Roberts SM, Arrey F, Münz C (2007) NK cell survival mediated through the regulatory synapse with human DCs requires IL-15Ralpha. J Clin Invest 117(11): 3316–29.
[28]
Mocikat R, Braumuller H, Gumy A, Egeter O, Ziegler H, et al. (2003) Natural killer cells activated by MHC class I(low) targets prime dendritic cells to induce protective CD8 T cell responses. Immunity 19(4): 561–9.
[29]
Mailliard RB, Son YI, Redlinger R, Coates PT, Giermasz A, et al. (2003) Dendritic cells mediate NK cell help for Th1 and CTL responses: two-signal requirement for the induction of NK cell helper function. J Immunol 171(5): 2366–73.
[30]
Boros P, Bromberg JS (2006) New cellular and molecular immune pathways in ischemia/reperfusion injury. Am J Transplant 6(4): 652–8.
[31]
Weiler M, Rogashev B, Einbinder T, Hausmann MJ, Kaneti J, et al. (1998) Interleukin-15, a leukocyte activator and growth factor, is produced by cortical tubular epithelial cells. J Am Soc Nephrol 9(7): 1194–201.
Strehlau J, Pavlakis M, Lipman M, Maslinski W, Shapiro M, et al. (1996) The intragraft gene activation of markers reflecting T-cell-activation and -cytotoxicity analyzed by quantitative RT-PCR in renal transplantation. Clin Nephrol 46(1): 30–3.
[34]
LaRosa DF, Rahman AH, Turka LA (2007) The innate immune system in allograft rejection and tolerance. J Immunol 178: 7503–7509.
[35]
Uhrberg M, Valiante NM, Shum BP, Shilling HG, Lienert-Weidenbach K, et al. (1997) Human diversity in killer cell inhibitory receptor genes. Immunity 7: 753–63.
[36]
Martinez OM, Rosen HR (2005) Basic concepts in transplant immunology. Liver Transpl 11(4): 370–81.
[37]
Crispe IN (2003) Hepatic T cells and liver tolerance. Nat Rev Immunol (3): 51–62.
[38]
Limmer A, Ohl J, Kurts C, Ljunggren HG, Reiss Y, et al. (2000) Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance. Nat Med 6(12): 1348–54.
[39]
Knolle PA, Schmitt E, Jin S, Germann T, Duchmann R, et al. (1999) Induction of cytokine production in naive CD4(+) T cells by antigen-presenting murine liver sinusoidal endothelial cells but failure to induce differentiation toward Th1 cells. Gastroenterology 116(6): 1428–40.
[40]
O'Connell PJ, Morelli AE, Logar AJ, Thomson AW (2000) Phenotypic and functional characterization of mouse hepatic CD8α+ lymphoid-related dendritic cells. J Immunol 165: 795–803.
[41]
Navarro V, Herrine S, Katopes C, Colombe B, Spain CV (2006) The effect of HLA-Class I (A and B) and class II (DR) compatibility on liver transplantation outcomes: an analysis of the OPTN database. Liver Transpl 12(4): 652–8.
[42]
Kitchens WH, Uehara S, Chase CM, Colvin RB, Russell PS, et al. (2006) The changing role of natural killer cells in solid organ rejection and tolerance. Transplantation 81(6): 811–7.
[43]
Obara H, Nagasaki K, Hsieh CL, Ogura Y, Esquivel CO, et al. (2005) IFN-gamma, produced by NK cells that infiltrate liver allografts early after transplantation, links the innate and adaptive immune responses. Am J Transplant 5(9): 2094–103.
[44]
Maier S, Tertilt C, Chambron N, Gerauer K, Hüser N, et al. (2001) Inhibition of natural killer cells results in acceptance of cardiac allografts in CD28？/？ mice. Nat Med 7: 557–562.
[45]
Uehara S, Chase CM, Kitchens WH, Rose HS, Colvin RB, et al. (2005) NK cells can trigger allograft vasculopathy: the role of hybrid resistance in solid organ allografts. J Immunol 175(5): 3424–30.
Baker RJ, Hernandez-Fuentes MP, Brookes PA, Chaudhry AN, Cook HT, et al. (2001) Loss of direct and maintenance of indirect alloresponses in renal allograft recipients: implications for the pathogenesis of chronic allograft nephropathy. J Immunol 167(12): 7199–206.
[48]
SivaSai KS, Smith MA, Poindexter NJ, Sundaresan SR, Trulock EP, et al. (1999) Indirect recognition of donor HLA class I peptides in lung transplant recipients with bronchiolitis obliterans syndrome. Transplantation 67(8): 1094–8.
[49]
Najafian N, Salama AD, Fedoseyeva EV, Benichou G, Sayegh MH (2002) Enzyme-linked immunosorbent spot assay analysis of peripheral blood lymphocyte reactivity to donor HLA-DR peptides: potential novel assay for prediction of outcomes for renal transplant recipients. J Am Soc Nephrol 13(1): 252–9.
[50]
Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, et al. (2000) Immunobiology of dendritic cells. Annu Rev Immunol 18: 767–811.
[51]
Walzer T, Dalod M, Robbins SH, Zitvogel L, Vivier E (2005) Natural-killer cells and dendritic cells: “l'union fait la force”. Blood 106(7): 2252–8.
[52]
Moretta A (2005) The dialogue between human natural killer cells and dendritic cells. Curr Opin Immunol 17(3): 306–11.
[53]
Cooper MA, Fehniger TA, Fuchs A, Colonna M, Caligiuri MA (2004) NK cell and DC interactions. Trends Immunol 25: 47–52.
[54]
Weiler M, Kachko L, Chaimovitz C, Van Kooten C, Douvdevani A (2001) CD40 ligation enhances IL-15 production by tubular epithelial cells. J Am Soc Nephrol 12: 80–87.
[55]
Baan CC, Knoop CJ, van Gelder T, Holweg CT, Niesters HG, et al. (1999) Anti-CD25 therapy reveals the redundancy of the intragraft cytokine network after clinical heart transplantation. Transplantation 67(6): 870–6.
[56]
Chiossone L, Vitale C, Cottalasso F, Moretti S, Azzarone B, et al. (2007) Molecular analysis of the methylprednisolone-mediated inhibition of NK-cell function: evidence for different susceptibility of IL-2- versus IL-15-activated NK cells. Blood 109(9): 3767–75.
[57]
Sánchez-Sánchez N, Riol-Blanco L, Rodríguez-Fernández JL (2006) The multiple personalities of the chemokine receptor CCR7 in dendritic cells. J Immunol 176(9): 5153–9.
[58]
Kellermann SA, Hudak S, Oldham ER, Liu YJ, McEvoy LM (1999) The CC chemokine receptor-7 ligands 6Ckine and macrophage inflammatory protein-3 beta are potent chemoattractants for in vitro- and in vivo-derived dendritic cells. J Immunol 162(7): 3859–64.
[59]
Riol-Blanco L, Sánchez-Sánchez N, Torres A, Tejedor A, Narumiya S, et al. (2005) The chemokine receptor CCR7 activates in dendritic cells two signaling modules that independently regulate chemotaxis and migratory speed. J Immunol 174(7): 4070–80.
[60]
Sánchez-Sánchez N, Riol-Blanco L, de la Rosa G, Puig-Kr？ger A, García-Bordas J, et al. (2004) Chemokine receptor CCR7 induces intracellular signaling that inhibits apoptosis of mature dendritic cells. Blood 104(3): 619–25.
[61]
Kapsenberg ML (2003) Dendritic-cell control of pathogen-driven T-cell polarization. Nat Rev Immunol 3(12): 984–93.
[62]
Coates PT, Duncan FJ, Colvin BL, Wang Z, Zahorchak AF, et al. (2004) In vivo-mobilized kidney dendritic cells are functionally immature, subvert alloreactive T-cell responses, and prolong organ allograft survival. Transplantation 77: 1080–1089.
[63]
Hawiger D, Inaba K, Dorsett Y, Guo M, Mahnke K, et al. (2001) Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J Exp Med 194(6): 769–79.
[64]
Borg C, Jalil A, Laderach D, Maruyama K, Wakasugi H, et al. (2004) NK cell activation by dendritic cells (DCs) requires the formation of a synapse leading to IL-12 polarization in DCs. Blood 104: 3267–3275.
[65]
Marcenaro E, Della Chiesa M, Bellora F, Parolini S, Millo R, et al. (2005) IL-12 or IL-4 prime human NK cells to mediate functionally divergent interactions with dendritic cells or tumors. J Immunol 174(7): 3992–8.
[66]
Hegde S, Pahne J, Smola-Hess S (2004) Novel immunosuppressive properties of interleukin-6 in dendritic cells: inhibition of NF-κB binding activity and CCR7 expression. FASEB Journal 18: 1439–1441.
[67]
Arend WP, Malyak M, Guthridge CJ, Gabay C (1998) Interleukin-1 receptor antagonist: role in biology. Annu Rev Immunol 16: 27–55.
